Phosphodiesterase inhibitors as immunomodulatory drugs
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abstract
Intracellular levels of cyclic nucleotides (cAMP and cGMP) play a critical role in many physiological processes of immune cells. Phosphodiesterases (PDEs) include a large group of related enzymes that have a pivotal role in the regulation of intracellular levels of cyclic nucleotides. Pentoxifylline (PTX) is a non-specific inhibitor of PDEs that shows many different effects on immune cells. The activation, cell proliferation, adhesion, polarisation and chemotaxis of T cells are down-regulated in vitro by PTX. This drug also inhibits the synthesis of different pro-inflammatory cytokines, mainly tumour necrosis factor-α. Accordingly, it has been found that PTX has a beneficial effect in vivo, in different immune-mediated and inflammatory conditions. On the other hand, rolipram is a potent PDE4-specific inhibitor that shows similar immunomodulatory and anti-inflammatory properties. In addition, rolipram has a down-regulatory effect on different phenomena involved in immediate hypersensitivity reactions, including the synthesis of Th2 cytokines, IgE production and the activation of basophils and eosinophils. PDE inhibitors are very interesting drugs with a great therapeutic potential for the treatment of immune-mediated and inflammatory diseases.
